IL‐4 induces proliferation in prostate cancer PC3 cells under nutrient‐depletion stress through the activation of the JNK‐pathway and survivin up‐regulation

Abstract

Interleukin (IL)-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumor microenvironment of cancer patients where it correlates with the grade of malignancy. The direct effect of IL-4 on cancer cells has been associated with increased cell survival; however, its role in cancer cell proliferation and related mechanisms is still unclear. Here it was shown that in a nutrient-depleted environment, IL-4 induces proliferation in prostate cancer PC3 cells. In these cells, under nutrient-depletion stress, IL-4 activates mitogen-activated protein kinases (MAPKs), including Erk, p38 and JNK. Using MAP-signaling-specific inhibitors, it was shown that IL-4-induced proliferation is mediated by JNK activation. In fact, JNK-inhibitor-V stunted IL-4-mediated cell proliferation. Furthermore, it was found that IL-4 induces survivin up-regulation in nutrient-depleted cancer cells. Using survivin-shRNAs, it was demonstrated that in this milieu survivin expression above a threshold limit is critical to the mechanism of IL-4-mediated proliferation. In addition, the significance of survivin up-regulation in a stressed environment was assessed in prostate cancer mouse xenografts. It was found that survivin knockdown decreases tumor progression in correlation with cancer cell proliferation. Furthermore, under nutrient depletion stress, IL-4 could induce proliferation in cancer cells from multiple origins: MDA-MB-231 (breast), A253 (head and neck), and SKOV-3 (ovarian). Overall, these findings suggest that in a tumor microenvironment under stress conditions, IL-4 triggers a simultaneous activation of the JNK-pathway and the up-regulation of survivin turning on a cancer proliferation mechanism.

The receptor NLRP3 is a transcriptional regulator of TH2 differentiation

“…Large amounts of T H 2 cytokines are observed in the tumor microenvironment and peripheral blood of patients with prostate, bladder and breast cancers [37][38][39] . IL-4 can directly induce the proliferation of colon, breast, head and neck, ovarian and prostate cancer cells in vitro [40][41][42] and can also activate myeloid cell-derived suppressor cells 43 or type 2 tumor-associated macrophages 44 and inhibit T H 1 polarization. We have now provided evidence that in mouse cancer models in which T H 2 cells accumulated in wild-type mice, deficiency in NLRP3 blunted the accumulation of T H 2 cells.…”

Interleukin-4 regulates macrophage polarization via the MAPK signaling pathway to protect against atherosclerosis

“…Haeng Park et al (2014) also confirmed that the anti-atherosclerotic effects of Polygonum aviculare L. ethanol extract in ApoE -/-mice are mediated via the MAPK pathway. Furthermore, high levels of IL-4 in the tumor microenvironment were observed, which could activate MAPKs, including ERK, p38, and JNK (Roca et al, 2012). Jiménez-Garcia et al (2015) demonstrated that p38 MAPK could play a pivotal role in IL-4-induced alternative activation of macrophages.…”

IL4 Receptor ILR4α Regulates Metastatic Colonization by Mammary Tumors through Multiple Signaling Pathways

“…The IL4/IL4R interaction has been shown to enhance the proliferation and survival of breast cancer cells in vitro [6,7], and the survival of other epithelial cancer cell types in vivo [4]. Still, there is no data regarding the influence of IL4R expression on the proliferation and survival of breast cancer cells in vivo , or on metastatic tumor growth in general.…”